A GLP‐1/glucagon (GCG)/CCK2 receptors tri‐agonist provides new therapy for obesity and diabetes

Background and Purpose Glucagon‐like peptide‐1 (GLP‐1) and glucagon (GCG) receptor dual agonist have promising therapeutic effects in the treatment of obesity and diabetes. Moreover, GLP‐1 and cholecystokinin 2 (CCK 2 ) dual agonists have been shown to restore pancreas function and improve glycaemic control in preclinical studies. We describe, for the first time, the beneficial effects of GLP‐1/glucagon receptor and GLP‐1/CCK 2 dual agonists, which can be integrated into one peptide, resulting in significant anti‐diabetes and anti‐obesity effectiveness. Experimental Approach The in vitro potency of this novel peptide Xenopus (x) GLP‐1/GCG/CCK 2 tri‐agonist ( x GLP/GCG/gastrin) against GLP‐1, GCG, CCK 1 and CCK 2 receptors was determined on cells expressing the corresponding receptors by cAMP accumulation or ERK1/2 phosphorylation assays. The in vivo anti‐diabetes and anti‐obesity effects of this tri‐agonist xGLP/GCG/gastrin were studied in both db/db and diet induced obesity (DIO) mice. Key Results xGLP/GCG/gastrin was a potent and selective GLP‐1, GCG and CCK 2 tri‐agonist. In DIO mice, the metabolic benefits of xGLP‐1/GCG/gastrin, such as reduction of body weight and hepatic lipid contents were significantly better than those of the peptide ZP3022 (GLP‐1/CCK‐2 dual agonist) and liraglutide. In a short‐term study in db/db mice, xGLP/GCG/gastrin treatment had considerable effects, increasing islet numbers, islet areas and insulin content. In a long‐term treatment study using db/db mice, xGLP‐1/GCG/gastrin showed a significantly and sustained improvement in glucose tolerance and glucose control compared with that of liraglutide, ZP3022, cotadutide (GLP‐1/GCG dual agonist) and xGLP/GCG‐15. Conclusions and Implications These results demonstrate the therapeutic potential of xGLP‐1/GCG/gastrin for the treatment of obesity and diabetes.